Recently, there has been developed a genetic recombination technique comprising using host cells containing complex DNA (deoxyribonucleic acid) composed of their vector plasmid or the like and a gene inserted thereinto having information sequence for a useful product, and allowing said cells to produce a large amount of the useful product. Human interferon and insulin, etc. are already being produced by using this technique, and Escherichia coli, yeasts, Bacillus subtilis, Actinomyces, animal cells, plant cells, etc. have heretofore been utilized as the host.
However, there has not yet been developed any process for industrially producing a large amount of a desired product by using recombinant cells having an objective gene, and, therefore, an efficient process for culturing recombinant cells is desired to be developed as soon as possible.
As one method for allowing recombinant cells to produce a large amount of a desired product, a rise in cell concentration in culture broth is considered. However, even when a substrate is fed in order to raise the cell concentration, cell growth stops in the course of culture and it becomes difficult to raise the cell concentration. Therefore, there has been provided a process in which in order to remove a cell growth inhibiting substance which causes the stop of cell growth, a culture broth is taken out intermittently or continuously and cells are recovered by centrifugation and charged into a culture tank again (Japanese Patent Application Kokai (Laid-Open) No. 29985/78). This process is intended for culturing yeasts to produce a large amount of cells themself and is not a process for culturing cells having complex DNA for allowing the cells to produce a desired product. In cultivation of baker's yeast, there is known a process comprising detecting the production of ethanol by measuring the respiratory quotient, feeding a substrate, and thereby raising the yeast concentration (Japanese Patent Application Kokai (Laid-Open) Nos. 36983/82 and 78584/83). However, this culture process is not a process for culturing cells having complex DNA.
On the other hand, as a process for culturing cells having complex DNA, there has been proposed a process in which cells are cultured at a temperature lower than the optimum growth temperature of the cells (Japanese Patent Application Kokai (Laid-Open) No. 141796/83). However, this culture process was developed without consideration of removal of the cell growth inhibiting substance which caused the stop of cell growth.